Novel indole derivatives

ABSTRACT

A heteroaryl derivative having the formula (I). The compounds of the invention are considered useful for the treatment of affective disorders such as general anxiety disorder, panic disorder, obsessive compulsive disorder, depression, social phobia and eating disorders, and neurological disorders such as psychosis.

The present invention relates to novel heteroaryl derivatives potentlybinding to the 5-HT_(1A) receptor, pharmaceutical compositionscontaining these compounds and the use thereof for the treatment ofcertain psychiatric and neurological disorders. Many of the compounds ofthe invention have also potent serotonin reuptake inhibition activityand are thus considered particularly useful for the treatment ofdepression.

Furthermore, many compounds of the invention have also effect atdopamine D₃ and D₄ receptors and are considered to be useful for thetreatment of psychosis.

BACKGROUND ART

Clinical and pharmacological studies have shown that 5-HT_(1A) agonistsand partial agonists are useful in the treatment of a range of affectivedisorders such as generalised anxiety disorder, panic disorder,obsessive compulsive disorder, depression and aggression.

It has also been reported that 5-HT_(1A) ligands may be useful in thetreatment of ischaemia.

An overview of 5-HT_(1A) antagonists and proposed potential therapeutictargets for these antagonists based upon preclinical and clinical dataare presented by Schechter et al. Serotonin 1997, Vol. 2, Issue 7. It isstated that 5-HT_(1A) antagonists may be useful in the treatment ofschizophrenia, senile dementia, dementia associated with Alzheimer'sdisease, and in combination with SSRI antidepressants also to be usefulin the treatment of depression.

5-HT reuptake inhibitors are well-known antidepressant drugs and usefulfor the treatment of panic disorders and social phobia.

The effect of combined administration of a compound that inhibitsserotonin reuptake and a 5-HT_(1A) receptor antagonist has beenevaluated in several studies mis, R. B. et al. Eur., J. Pharmacol. 1987,143, p 195-204 and Gartside, S. E. Br. J. Pharmacol. 1995, 115, p1064-1070, Blier, P. et al. Trends Pharmacol. Sci. 1994, 15, 220). Inthese studies it was found that combined 5-HT_(1A) receptor antagonistsand serotonin reuptake inhibitors would produce a more rapid onset oftherapeutic action.

Dopamine D₄ receptors belong to the family of dopamine D₂-like receptorswhich is considered to be responsible for the antipsychotic effects ofneuroleptics. Dopamine D₄ receptors are primarily located in areas ofthe brain other than striatum, suggesting that dopamine D₄ receptorligands have antipsychotic effect and are devoid of extrapyramidalactivity.

Accordingly, dopamine D₄ receptor ligands are potential drugs for thetreatment of psychosis and positive symptoms of schizophrenia andcompounds with combined effects at dopamine D₄, and serotonergicreceptors may have the further benefit of improved effect on negativesymptoms of schizophrenia, such as anxiety and depression, alcoholabuse, impulse control disorders, aggression, side effects induced byconventional antipsychotic agents, ischaemic disease states, migraine,senile dementia and cardiovascular disorders and in the improvement ofsleep.

Dopamine D₃ receptors also belong to the family of dopamine D₂-likereceptors. D₃ antagonistic properties of an antipsychotic drug couldreduce the negative symptoms and cognitive deficits and result in animproved side effect profile with respect to EPS and hormonal changes.

Accordingly, agents acting on the 5-HT_(1A) receptor, both agonists andantagonists, are believed to be of potential use in the therapy ofpsychiatric and neurological disorders and thus being highly desired.Furthermore, antagonists, at the same time having potent serotoninreuptake inhibition activity and/or D₄ and/or D₃ activity, may beparticularly useful for the treatment of various psychiatric andneurological diseases.

Previously, closely related structures have been reported:

WO 9955672 discloses a general formula in which indole derivativeshaving 5-HT_(1A) receptor and D₂ receptor affinity are included

EP 900792 discloses a general formula in which indole derivatives areembraced as 5-HT_(1A) and 5-HT_(1D) as well as D₂ receptor ligands.

It has now been found that a class of indole derivatives is particularlyuseful as 5-HT_(1A) ligands. Furthermore, it has been found that many ofthese compounds have other highly beneficial properties as e.g. potentserotonin reuptake inhibition activity and/or affinity for the D₄receptor.

SUMMARY OF THE INVENTION

The invention comprises the following:

A compound represented by the general formula I

whereinA represents O or S;n is 2, 3, 4, 5, 6, 7, 8, 9 or 10;m is 2 or 3;W represents N, C or CH;Q represents N, C or CH;and the dotted line represents an optional bond;R¹ represents hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl-C₁₋₆-alkyl or acyl;R², R³, R⁴, R⁵ and R⁶ independently represent hydrogen, halogen, cyano,nitro, C₁₋₆-alkyl, C₁₋₆alkoxy, C₁₋₆-alkylsulfanyl, C₁₋₆ alkylsulfonyl,hydroxy, hydroxy-C₁₋₆-alkyl, C₁₋₆alkoxycarbonyl, acyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₄-alkyl, trifluoromethyl, trifluoromethoxy, NR¹⁵R¹⁶wherein R¹⁵ and R¹⁶ independently represent hydrogen, C₁₋₆-alkyl,C₃₋₈-cycloalkyl or phenyl; or R¹⁵ and R¹⁶ together with the nitrogen towhich they are attached form a 5- or 6-membered ring optionallycontaining one further heteroatom;R⁷ and R^(7′) independently represent hydrogen or C₁₋₆-alkyl or maytogether form a bridge consisting of two or three methylene groups;R⁸, R⁹, R¹⁰ and R¹¹ are each independently selected from hydrogen,halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,phenyl, thiophenyl, C₁₋₆-alkoxy, C₁₋₆-alkylsulfanyl, C₁₋₆-alkylsulfonyl,hydroxy, formyl, acyl, acylamino, aminocarbonyl,C₁₋₆-alkoxycarbonylamino, aminocarbonylamino,C₁₋₆-alkylaminocarbonylamino and di(C₁₋₆-alkyl)aminocarbonylamino,NR¹³R¹⁴ wherein R¹³ and R¹⁴ independently represent hydrogen,C₁₋₆-alkyl, C₃₋₈-cycloalkyl or phenyl; or R¹³ and R¹⁴ together with thenitrogen to which they are attached form a 5- or 6-membered carbocyclicring optionally containing one further heteroatom;its enantiomers, and a pharmaceutically acceptable acid addition saltthereof.

The invention also relates to a pharmaceutical composition comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofand at least one pharmaceutically acceptable carrier or diluent.

In a further embodiment, the invention relates to the use of a compoundof formula (I) or a pharmaceutically acceptable acid addition saltthereof for the preparation of a medicament for the treatment of adisorder or disease responsive to the inhibition of serotonin uptake andantagonism of 5-HT^(1A) receptors.

In a further embodiment, the invention relates to the use of a compoundof formula (I) or a pharmaceutically acceptable acid addition saltthereof for the preparation of a medicament for the treatment of adisorder or disease responsive to the combined effect of 5-HT_(1A)receptors and dopamine D₄ receptors.

In particular, the invention relates to the use of a compound accordingto the invention or a pharmaceutically acceptable acid addition saltthereof for the preparation of a medicament for the treatment ofaffective disorders such as general anxiety disorder, panic disorder,obsessive compulsive disorder, depression, social phobia and eatingdisorders; other psychiatric disorders such as psychosis andneurological disorders.

In still another embodiment, the present invention relates to a methodfor the treatment of a disorder or disease of living animal body,including a human, which is responsive to the inhibition of serotoninuptake and antagonism of 5-HT_(1A) receptors comprising administering tosuch a living animal body, including a human, a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable acid addition salt thereof.

In still another embodiment, the present invention relates to a methodfor the treatment of a disorder or disease of living animal body,including a human, which is responsive to the effect of 5-HT_(1A) and D₄receptors comprising administering to such a living animal body,including a human, a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable acid addition salt thereof.

Due to their combined antagonism of 5-HT_(1A) receptors and serotoninreuptake inhibiting effect, the compounds of the invention areconsidered particularly useful as fast onset of action medicaments forthe treatment of depression. The compounds may also be useful for thetreatment of depression in patients who are resistant to treatment withcurrently available antidepressants.

The compounds of the invention have high affinity for the 5-HT_(1A) andD₄ receptors. Accordingly, the compounds of the invention are considereduseful for the treatment of affective disorders such as general anxietydisorder, panic disorder, obsessive compulsive disorder, depression,social phobia and eating disorders; other psychiatric disorders such aspsychosis and neurological disorders.

DETAILED DESCRIPTION OF THE INVENTION

In preferred embodiments of the invention, n is 2, 3 or 4

In preferred embodiments of the invention, W represents N;

In preferred embodiments of the invention, Q represents N;

In preferred embodiments of the invention, Q represents C or CH;

In preferred embodiments of the invention, R⁷ and R^(7′) are bothhydrogen;

In preferred embodiments of the invention, R¹ is hydrogen;

In preferred embodiments of the invention, R², R³, R⁴, R⁵ and R⁶represent hydrogen;

In preferred embodiments of the invention, R⁸, R⁹, R¹⁰ and R¹¹independently represent hydrogen, halogen, C₁₋₆-alkyl, C₃₋₈-cycloalkyl,CN, CF₃, OCF₃, NH₂, NR¹³R¹⁴ wherein R¹³ and R¹⁴ independently representhydrogen, C₁₋₆-alkyl, C₃₋₈-cycloalkyl or phenyl; or R¹³ and

R¹⁴ together with the nitrogen form a piperidine or pyrrolidine;

In more preferred embodiments of the invention, R⁸, R⁹, R¹⁰, R¹¹ and R¹²independently represent methyl, cyclopropyl, trifluoromethyl, cyano,chloro, bromo, piperidinyl, phenyl;

In a preferred embodiment of the invention, the compounds of formula Ias described above are:

-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4,6-dimethylnicotinonitrile,    1a-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-6-(thiophen-2-yl)-4-trifluoromethylnicotinonitrile,    1b-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}pyridine, 1c-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-6-methylnicotinonitrile,    1d-   3-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-2-chloropyridine, 1e-   3-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-2-bromopyridine, 1f-   3-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-2-methylpyridine, 1g-   3-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-5-chloropyridine, 1h-   2-{4-[4-(1H-Indol-4-yl)piperazin-1-yl]butylsulfanyl}-5-trifluoromethylpyridine,    1i-   2-{4-[4-(1H-Indol-4-yl)piperazin-1-yl]butylsulfanyl}-4,6-dimethylnicotinonitrile,    1j-   2-{3-[4-(1H-Indol-4-yl)piperazin-1-yl]propylsulfanyl}-5-trifluoromethylpyridine,    1k-   2-{3-[4-(1H-Indol-4-yl)piperazin-1-yl]propylsulfanyl}-4,6-dimethylnicotinonitrile,    1l-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-6-methylnicotinamide,    2a-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}nicotinonitrile,    2b-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4-methylpyridine,    2c-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4-methyl-6-(piperidin-1-yl)nicotinonitrile,    2d-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4-trifluoromethyl-6-cyclopropylnicotinonitrile,    2e-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-3-methanesulfonyl-4-methyl-6-phenylpyridine,    2f-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}nicotinonitrile, 2g-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-4-methylpyridine, 2h-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-6-methylnicotinamide,    2i-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-4-methyl-6-(piperidin-1-yl)nicotinonitrile,    2j-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-4-trifluoromethyl-6-cyclopropylnicotinonitrile,    2k-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-3-methanesulfonyl-4-methyl-6-phenylpyridine,    2l-   6-Chloro-2-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4-methylnicotinonitrile,    2m-   6-Chloro-5-fluoro-2-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}nicotinonitrile,    2n-   4,6-Dimethyl-2-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}pyrimidine,    2o-   5-Cyano-4-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}pyrimidine,    2p-   5-Cyano-4-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}-6-methylsulfanyl-2-phenylpyrimidine,    2q-   5-Ethyl-2-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}pyrimidine,    2r-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4-trifluoromethylpyrimidine,    2s    or a pharmaceutical acceptable salt thereof.    Definition of Substituents etc.

The term C₁₋₆ alkyl refers to a branched or linear alkyl group havingfrom one to six carbon atoms inclusive, including, but not limited to,methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyland 2-methyl-1-propyl.

Similarly, C₂₋₆ alkenyl and C₂₋₆ alkynyl, respectively, designate suchgroups having from two to six carbon atoms inclusive wherein the groupsare having at least one double bond or triple bond, respectively.

The terms C₁₋₆-alkoxy, C₁₋₆ alkylsulfanyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylamino, C₁₋₆ alkylcarbonyl, hydroxy-C₁₋₆-alkyl etc. designate suchgroups in which the C₁₋₆ alkyl is as defined above.

The term C₃₋₈ cycloalkyl designates a monocyclic or bicyclic carbocyclehaving three to eight C-atoms, including, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The term aryl refers to a carbocyclic aromatic group, such as phenyl,naphthyl, in particular phenyl. As used herein, aryl may be substitutedone or more times with halogen, nitro, cyano, trifluoromethyl,C₁₋₆-alkyl, hydroxy and C₁₋₆-alkoxy.

Halogen means fluoro, chloro, bromo or iodo.

As used herein, the term acyl refers to formyl, C₁₋₆-alkylcarbonyl,arylcarbonyl, aryl-C₁₋₆-alkylcarbonyl wherein the aryl is as definedabove, C₃₋₈-cycloalkylcarbonyl or a C₃₋₈-cycloalkyl-C₁₋₆alkyl-carbonylgroup.

The term aminocarbonyl means —CO-amino wherein amino is defined asabove.

The term acylamino means a group of the formula —NHCOH,—NHCO—C₁₋₆-alkyl, —NHCO-aryl, —NHCO—C₃₋₈-cycloalkyl,—NHCO—C₃₋₈-cycloalkyl-C₁₋₆-alkyl, wherein the alkyl, cycloalkyl and arylare as defined above.

The terms aminocarbonylamino, C₁₋₆-alkylaminocarbonylamino anddi(C₁₋₆-alkyl)aminocarbonylamino mean a group of the formula NHCONH₂,—NHCONHC₁₋₆-alkyl, NHCON(di-C₁₋₆-alkyl), respectively.

The acid addition salts of the invention are preferably pharmaceuticallyacceptable salts of the compounds of the invention formed with non-toxicacids. Exemplary of such organic salts are those with maleic, fumaric,benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic,methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric,salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic,citraconic, aspartic, stearic, palmitic, itaconic, glycolic,p-aminobenzoic, glutamic, benzenesulfonic, and theophylline aceticacids, as well as the 8-halotheophyllines, for example8-bromotheophylline. Exemplary of such inorganic salts are those withhydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitricacids.

Further, the compounds of this invention may exist in unsolvated as wellas in solvated forms with pharmaceutically acceptable solvents such aswater, ethanol and the like. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thisinvention.

Some of the compounds of the present invention contain chiral centresand such compounds exist in the form of isomers (e.g. enantiomers). Theinvention includes all such isomers and any mixtures thereof includingracemic mixtures.

Racemic forms can be resolved into the optical antipodes by knownmethods, for example by separation of diastereomeric salts thereof withan optically active acid, and liberating the optically active aminecompound by treatment with a base. Another method for resolvingracemates into the optical antipodes is based upon chromatography on anoptically active matrix. Racemic compounds of the present invention canalso be resolved into their optical antipodes, e.g. by fractionalcrystallization of d- or l-(tartrates, mandelates or camphorsulphonate)salts for example. The compounds of the present invention may also beresolved by the formation of diastereomeric derivatives.

Additional methods for the resolution of optical isomers, known to thoseskilled in the art, may be used. Such methods include those discussed byJ. Jaques, A. Collet and S. Wilen in “Enantiomers, Racemates, andResolutions”, John Wiley and Sons, New York (1981).

Optically active compounds can also be prepared from optically activestarting materials.

Finally, formula (I) includes any tautomeric forms of the compounds ofthe invention.

The compounds of the invention can be prepared by one of the followingmethods comprising:a) treating a compound of formula (II) with a compound of formula (I inthe presence of a reducing agent.

wherein n, m, R¹-R¹¹, Q, W, A and the dotted line are as defined above;b) treating a compound of formula (IV) with a compound of formula (V) inthe presence of an appropriate base

wherein L is a suitable leaving group such as e.g. chloro and n, m,R¹-R¹², Q, W, A and the dotted line are as defined above.

The compounds of formula (I) are isolated as the free base or in theform of a pharmaceutically acceptable salt thereof.

The reductive amination according to method a) is preferably carried outin an inert organic solvent such as dimethylformamide or tetrahydrofuranin the presence of a reducing agent, e.g. triacetoxyborohydride, at roomtemperature.

The arylation according to method b) is conveniently performed in aninert organic solvent such as dimethylformamide in the presence of abase (e.g. potassium tert-butoxide) at a temperature in the range of40-100° C., preferably in the range of 40-80° C. and most preferredaround 50° C.

Preparation of indolyl piperazines and tetrahydropyridyl piperazines offormula ([I) is described in WO 9967237. Aldehydes of formula (II) areprepared as described in the Examples below. Alcohols and mercaptans offormula (V) are prepared as described in the Examples below. Thestarting chloropyridines of formula (IV) are commercially available ormade by methods well-described in the literature

The following examples will illustrate the invention further. They are,however, not to be construed as limiting.

EXAMPLES

Melting points were determined on a Btichi SMP-20 apparatus and areuncorrected. Analytical LC-MS data were obtained on a PE Sciex API 150EXinstrument equipped with IonSpray source (method D) or heated nebulizer(APCI, methods A and B) and Shimadzu LC-8A/SLC-10A LC system. The LCconditions [30×4.6 mm YMC ODS-A with 3.5 μm particle size] were lineargradient elution with water/acetonitrile/trifluoroacetic acid(90:10:0.05) to water/acetonitrile/trifluoroacetic acid (10:90:0.03) in4 min at 2 mL/min. Purity was determined by integration of the UV trace(254 nm). The retention times R_(t) are expressed in minutes.

Mass spectra were obtained by an alternating scan method to givemolecular weight information. The molecular ion, MH+, was obtained atlow orifice voltage (5-20V) and fragmentation at high orifice voltage(100V).

Preparative LC-MS-separation was performed on the same instrument. TheLC conditions (50×20 mm YMC ODS-A with 5 μm particle size) were lineargradient elution with water/acetonitrile/trifluoroacetic acid(80:20:0.05) to water/acetonitrile/trifluoroacetic acid (10:90:0.03) in7 min at 22.7 mL/min. Fraction collection was performed by split-flow MSdetection.

¹H NMR spectra were recorded at 500.13 MHz on a Bruker Avance DRX500instrument or at 250.13 MHz on a Bruker AC 250 instrument. Deuteratedchloroform (99.8% D) or dimethyl sulfoxide (99.9% D) were used assolvents. TMS was used as internal reference standard. Chemical shiftvalues are expressed in ppm-values. The following abbreviations are usedfor multiplicity of NMR signals: s=singlet, d=doublet, t=triplet,q=quartet, qui=quintet, h=heptet, dd=double doublet, dt=double triplet,dq=double quartet, t=triplet of triplets, m=multiplet, b=broad singlet.NMR signals corresponding to acidic protons are generally omitted.Content of water in crystalline compounds was determined by Karl Fischertitration. Standard workup procedures refer to extraction with theindicated organic solvent from proper aqueous solutions, drying ofcombined organic extracts (anhydrous MgSO₄ or Na₂SO₄), filtering andevaporation of the solvent in vacuo. For column chromatography silicagel of type Kieselgel 60, 230-400 mesh ASTM was used. For ion-exchangechromatography (SCX, 1 g, Varian Mega Bond Elut®, Chrompack cat. no.220776). Prior use the SCX-columns were pre-conditioned with 10%solution of acetic acid in methanol (3 mL).

Example 1 4,6-Dimethyl-2-(2-oxo-ethylsulfanyl)-nicotinonitrile

4,6-Dimethyl-2-mercaptonicotinonitrile (3.0 g) was dissolved in DMF (40mL) and a solution of potassium tert-butoxide (19.2 mL; 1 M) intert-butanol added. The mixture was stirred for 10 min, added dropwiseto a solution of bromoacetaldehyd-dimethylacetal (3.2 g) in DMF (10 mL)and stirred over night at 70° C. The mixture was poured on water andextracted with ethyl acetate, the combined organic phases dried andevaporated to give an oil (5.3 g) which was dissolved in dioxane (40mL), HCl (20 mL; 3 M) was added and the mixture was stirred at 30° C.for 2 h. NaHCO₃ was added until pH reached 5-6, the mixture wasextracted with ethyl acetate, the combined organic phases dried withNa₂SO₄ and evaporated to give the title compound as an oil (2.9 g). ¹HNMR (CDCl₃): δ 2.45 (s, 6H); 3.35 (d, 2H); 6.85 (s, 1H); 9.55 (t, 1H).

2-{2-[4-(1H-Indol-4-yl-piperazin-1-yl]ethylsuofanyl}-4,6-dimethylnicotinonitrile1a

4,6-Dimethyl-2-(2-oxo-ethylsulfanyl)nicotinonitrile (2.9 g) wasdissolved in 1,2-dichloroethane (150 mL), a solution of1-(1H-indol-4-yl)piperazine (2.4 g) in DMF (150 mL) was added, sodiumtriacetoxyborohydride (14.9 g) was then added followed by stirring for 2h. The mixture was poured on water and Na₂CO₃ added until pH reached7-8. The mixture was extracted with ethyl acetate, the combined organicphases dried and evaporated to give an oil which was subjected topurification by column chromatography (silica gel; ethyl acetate andheptane) giving an oil which precipitated as the oxalate salt (0.36 g)from acetone. LC/MS (m/z) 392 (MH+), RT=1.92, purity: 99%.

In a similar manner the following compounds were prepared:

-   2-{2-[4(1H-Indol-4-yl)piperazin-1-yl]ethylsuyanyl}-6-(thiophen-2-yl)-4-trifluoromethylinicotinonitrile,    1b: LC/MS (m/z) 514 (MH+), RT=2.54, purity: 100%.-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}ypyridine, 1c:    LC/S (m/z) 339 (MH+), RT=1.58, purity: 83%.-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-6-methylnicotinonitrile,    1d: LC/MS (m/z) 378 (MH+), RT=1.95, purity: 92%.-   3-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-2-chloropyridine, 1e:    LC/MS (m/z) 357 (MH+), RT=1.50, purity: 93%.-   3-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-2-bromopyridine, 1f:    LC/MS (m/z) 403 (MH+), RT=1.54, purity: 89%.-   3-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-2-methylpyridine, 1g:    LC/MS (m/z) 337 (MH+), RT=0.71, purity: 78%.-   3-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-5-chloropyridine, 1h:    LC/MS (m/z) 357 (MH+), RT=1.58, purity: 100%.-   2-{4-[4-(1H-Indol-4-yl)piperazin-1-yl]butylsulfanyl}-5-trifluoromethylpyridine,    1i: LC/MS (m/z) 435 (MH+), RT=2.14, purity: 80%.-   2-{4-[4-(1H-Indol-4-yl)piperazin-1-yl]butylsulfanyl}-4,6-dimethylnicotinonitrile,    1j: LC/MS (m/z) 420 (MH+), RT=2.07, purity: 75%.-   2-{3-[4-(1H-Indol-4-yl)piperazin-1-yl]propylsulfanyl}-5-trifluoromethylpyridine,    1k: LC/MS (m/z) 421 (MH+), RT=2.06, purity: 98%.-   2-{3-[4-(1H-Indol-4-yl)piperazin-1-yl]propylsulfanyl}-4,6-dimethylnicotitionitrile,    1l: LC/MS (m/z) 406 (MH+), RT=1.99, purity: 100%.

Example 2 2-[4-(1H-Indol-4-yl)-piperazin-1-yl]-ethanethiol

1-(1H-Indol-4-yl)piperazine (3.9 g) and thiirane (1.75 g) was dissolvedin DMF (200 mL) and refluxed for 1 h. The mixture was evaporated andre-dissolved in TBF, dried with MgSO₄, filtered and evaporated to givethe an oil which was subjected to purification by column chromatography(silica gel; ethyl acetate and heptane) giving the title compound as anoil (2,2 g). MS m/z (%): 261 (MH+, 100%), 202 (100%), 159 (23%).

2-{2-[4(1H-Indol-4-yl)piperazin-1-yl-ethylsulfanyl}-6-methylnicotinonitrile,2a

2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethanethiol (2.2 g) was dissolved ina solution of potassium tert-butoxide (0.81 g) in DMF (25 mL), stirredfor 15 min and heated to 50° C. A solution of6-methyl-2-chloronicotinonitrile (1.91 g) in DMF (25 mL) was added dropwise and stirring was continued for another 2 h at 50° C. The mixturewas evaporated and re-dissolved in THF, washed with brine, dried withMgSO₄, filtered and evaporated to give an oil which was subjected topurification by column chromatography (silica gel; ethyl acetate,heptane and triethyl amine) giving the title compound as an oil whichprecipitated as the oxalate salt from acetone. LC/MS (m/z) 396 (MH+),RT=1.46, purity: 91%.

In a similar manner the following compounds were prepared:

-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}nicotinonitrile,    2b: LC/MS (m/z) 364 (MH+), RT=1.66, purity: 96%.-   2-{2-[4-(]H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4-methylpyridine,    2c: LC/MS (m/z) 353 M+), RT=1.70, purity: 87%.-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4-methyl-6-(piperidin-1-yl)nicotinonitrile,    2d: LC/MS (m/z) 461 (MH+), RT=2.29, purity: 95%.-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4-trifluoromethyl-6-cyclopropylnicotinonitrile,    2e: LC/MS (m/z) 472 (MH+), RT=2.33, purity: 94%.-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-3-methanesulfonyl-4-methyl-6-phenylpyridine,    2f: LC/MS (m/z) 507 (MH+), RT=2.16, purity: 92%.-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}nicotinonitrile, 2g:    LC/MS (m/z) 348 (MH+), RT=1.46, purity: 88%.-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-4-methylpyridine, 2h:    LC/MS (m/z) 337 (MH+), RT=1.66, purity: 100%.-   2-{2-[4-(]H-Indol-4-yl)piperazin-1-yl]ethoxy}-6-methylnicotinamide,    2i: LC/MS (m/z) 380 (MH+), RT=1.41, purity: 96%.-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy)-4-methyl-6-(piperidin-1-yl)nicotinonitrile,    2j: LC/MS (m/z) 445 (MH+), RT=2.24, purity: 100%.-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-4-trifluoromethyl-6-cyclopropylnicotinonitrile,    2k: LC/MS (m/z) 456 (MH+), RT=2.20, purity: 100%.-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-3-methanesulfonyl-4-methyl-6-phenylpyridine,    2l: LC/MS (m/z) 491 (MH+), RT=2.16, purity: 70%.-   6-Chloro-2-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4-methylnicotinonitrle,    2m: LC/MS (m/z) 413 (H+), RT=2.00, purity: 69%.-   6-Chloro-n-fluoro-2-(2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}nicotinonitrile,    2n: LC/MS (m/z) 417 (M+), RT=1.91, purity: 85%.-   2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}pyrimidine, 2o:    LC/MS (m/z) 368 (MH+), RT=1.62, purity: 73%.-   5-Cyano-4-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}pyrimidine,    2p: LC/MS (m/z) 365 (MH+), RT=1.62, purity: 90%.-   5-Cyano-4-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsuyfanyl}-6-methylsulfanyl-2-phenylpyrimidine,    2q: LC/MS (m/z) 488 (MH+), RT=2.49, purity: 93%.-   5-Ethyl-2-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}pyrimidine,    2r: LC/MS (m/z) 368 (MH+), RT=1.79, purity: 72%.-   2-{2-[4-(2H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4-trifluoromethylpyrimidine,    2s: LC/MS (m/z) 408 (MH+), RT=1.91, purity: 79%.    Pharmacological Testing

The affinity of the compounds of the invention to 5-HT_(1A) receptorswas determined by measuring the inhibition of binding of a radioactiveligand at 5-HT_(1A) receptors as described in the following test:

Inhibition of ³H-5-CT Binding to Human 5-HT_(1A) Receptors.

By this method, the inhibition by drugs of the binding of the 5-HT_(1A)agonist ³H-5-carboxamido tryptamine (3H-5-CT) to cloned human 5-HT_(1A)receptors stably expressed in transfected HeLa cells (HA7) (Fargin, A.et al. J. Biol. Chem. 1989, 264, 14848) is determined in vitro. Theassay was performed as a modification of the method described byHarrington, M. A. et al. J. Pharmacol. Exp. Ther. 1994, 268, 1098. Human5-HT_(1A) receptors (40 μg of cell homogenate) were incubated for 15minutes at 37° C. in 50 mM Tris buffer at pH 7.7 in the presence of³H-5-CT. Non-specific binding was determined by including 10 μM ofmetergoline. The reaction was terminated by rapid filtration throughUnifilter GF/B filters on a Tomtec Cell Harvester. Filters were countedin a Packard Top Counter. Compounds 1d, 2b, 2e and 2o were tested andshowed IC₅₀ values of less than 50 nM.

The compounds of the invention have also been tested for their effect onre-uptake of serotonin in the following test:

Inhibition of ³H-5-HT Uptake Into Rat Brain Synaptosomes.

Using this method, the ability of drugs to inhibit the accumulation of³H-5-HT into whole rat brain synaptosomes is determined in vitro. Theassay was performed as described by Hyttel, J. Psychopharmacology 1978,60, 13. Compounds 1a, 1d, 1l, 2b, 2e and 2o were tested and showed IC₅₀values of less than 20 nM.

The 5-HT_(1A) antagonistic activity of some of the compounds of theinvention has been estimated in vitro at cloned 5-HT_(1A) receptors,stably expressed in transfected HeLa cells (HA7). In this test,5-HT_(1A) antagonistic activity is estimated by measuring the ability ofthe compounds to antagonize the 5-HT induced inhibition of forskolininduced cAMP accumulation. The assay was performed as a modification ofthe method described by Pauwels, P. J. et al. Biochem. Pharmacol. 1993,45, 375. Compounds 1a, 1d, 1l, 2b and 2e were tested and showed IC₅₀values of less than 7000 nM.

Some of the compounds of the invention have also been tested for theirin vivo effect on 5-HT_(1A) receptors in the assay described by Sanchez.C. et al. Eur. J. Pharmacol. 1996, 315, pp 245. In this test,antagonistic effects of test compounds are determined by measuring theability of the test compounds to inhibit 5-MeO-DMT induced 5-HTsyndrome.

The compounds of the present invention possess valuable activity asserotonin re-uptake inhibitors and have antagonistic effect at 5-HT_(1A)receptors. The compounds of the invention are therefore considereduseful for the treatment of diseases and disorders responsive to theinhibition of serotonin re-uptake and antagonistic activity at 5-HT_(1A)receptors. Diseases responsive to the inhibition of serotonin re-uptakeare well-known in the art and include affective disorders, such asdepression, psychosis, anxiety disorders including general anxietydisorder, panic disorder, obsessive compulsive disorder, etc.

As explained above, the antagonistic activity at 5-HT_(1A) receptors ofthe compounds of the invention will counteract the negative feed backmechanism induced by the inhibition of serotonin reuptake and is therebyexpected to improve the effect of the serotonin reuptake inhibitingactivity of the compounds of the invention.

The compounds as claimed herein are therefore considered to beparticularly useful as fast onset of action medicaments for thetreatment of depression. The compounds may also be useful for thetreatment of depressions which are non-responsive to currently availableSSRIs.

Some of the compounds of the invention have also been found to haveaffinity to dopamine D₃ and D₄ receptors in the following two assays.

Inhibition of the Binding of ³H-YM-09151-2 to Human Dopamine D₄Receptors

By this method, the inhibition by drugs of the binding of [³H]YM-09151-2(0.06 nM) to membranes of human cloned dopamine D_(4.2) receptorsexpressed in CHO-cells is determined in vitro. Method modified from NENLife Science Products, Inc., technical data certificate PC2533-10/96.

Inhibition of the Binding of [³H]-Spiperone to Human D₃ Receptors

By this method, the inhibition by drugs of the binding [³H]Spiperone(0.3 nM) to membranes of human cloned dopamine D3-receptors expressed inCHO-cells is determined in vitro. Method modified from R. G. MacKenzieet al. Eur. J. Pharm.-Mol. Pharm. Sec. 1994, 266, 79-85.

Some of the compounds of the invention have also been tested for theirin vivo effect on 5-HT_(1A) receptors in the assay described by Sanchez,C. et al. Eur. J. Pharmacol. 1996, 315, pp 245. In this test,antagonistic effects of test compounds are determined by measuring theability of the test compounds to inhibit 5-MeO-DMT induced 5-HTsyndrome.

Accordingly, as the compounds of the invention show affinities in thedescribed tests, they are considered useful in the treatment ofaffective disorders, such as depression, generalised anxiety disorder,panic disorder, obsessive compulsive disorders, social phobia and eatingdisorders, and neurological disorders such as psychosis.

1. A compound represented by the formula I

wherein A represents O or S; n is 2,3,4,5,6,7, 8, 9 or 10; m is 2 or 3;W represents N, C or CH; Q represents N, C or CH; and the dotted linerepresents an optional bond; R¹ represents hydrogen, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl-C₁₋₆-alkylor acyl; R², R³, R⁴, R⁵ and R⁶ independently represent hydrogen,halogen, cyano, nitro, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylsulfanyl, C₁₋₆alkylsulfonyl, hydroxy, hydroxy-C₁₋₆-alkyl, C₁₋₆-alkoxycarbonyl, acyl,C₃₋₈-cycloalkyl, C₃-s-cycloalkyl-C₁₋₆-alkyl, trifluoromethyl,trifluoromethoxy, NR¹⁵R¹⁶ wherein R¹⁵ and R¹⁶ independently representhydrogen, C₁₋₆-alkyl, C₃₋₈-cycloalkyl or phenyl; or R¹⁵ and R¹⁶ togetherwith the nitrogen to which they are attached form a 5- or 6-memberedring optionally containing one further heteroatom; R⁷ and R^(7′)independently represent hydrogen or C₁₋₆-alkyl or may together form abridge consisting of two or three methylene groups; R⁸, R⁹, R¹⁰ and R¹¹are each independently selected from hydrogen, halogen, nitro, cyano,trifluoromethyl, trifluoromethoxy, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, phenyl,thiophenyl, C₁₋₆-alkoxy, C₁₋₆-alkylsulfanyl, C₁₋₆-alkylsulfonyl,hydroxy, formyl, acyl, acylamino, aminocarbonyl,C₁₋₆-alkoxycarbonylamino, aminocarbonylamino,C₁₋₆-alkylaminocarbonylamino and di(C₁₋₆-alkyl)amino-carbonylamino,NR¹³R¹⁴ wherein R¹³ and R¹⁴ independently represent hydrogen,C₁₋₆-alkyl, C₃₋₈-cycloalkyl or phenyl; or R¹³ and R¹⁴ together with thenitrogen to which they are attached form a 5- or 6-membered ringoptionally containing one further heteroatom; or an enantiomer orpharmaceutically acceptable acid addition salt thereof.
 2. The compoundaccording to claim 1, wherein n is 2, 3 or
 4. 3. The compound accordingto claim 1, wherein W represents N.
 4. The compound according to claim1, wherein R⁷ and R^(7′) are both hydrogen.
 5. The compound according toclaim 1, wherein R¹ is hydrogen.
 6. The compound according to claim 1,wherein R², R³, R⁴, R⁵ and R⁶ represent hydrogen.
 7. The compoundaccording to claim 1, wherein R⁸, R⁹, R¹⁰ and R¹¹ independentlyrepresent hydrogen, halogen, C₁₋₆-alkyl, C₃₋₈-cycloalkyl, CN, CF₃, OCF₃,NH₂, NR¹³R¹⁴ wherein R¹³ and R¹⁴ independently represent hydrogen,C₁₋₆-alkyl, C₃₋₈-cycloalkyl or phenyl; or R¹³ and R¹⁴ together with thenitrogen form a piperidine or pyrrolidine.
 8. The compound according toclaim 7, wherein R⁸, R⁹, R¹⁰ and R¹¹ independently represent methyl,cyclopropyl, trifluoromethyl, cyano, chloro, bromo, piperidinyl, phenyl.9. The compound according to claim 1, wherein said compound of formula Iis a member selected from the group consisting of:2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4,6-dimethylnicotinonitrile,1a,2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-6-(thiophen-2-yl)-4-trifluoromethylnicotinonitrile,1b, 2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}pyridine, 1c,2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-6-methylnicotinonitrile,1d, 3-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-2-chloropyridine, 1e,3-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-2-bromopyridine, 1f,3-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-2-methylpyridine, 1g,3-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-5-chloropyridine, 1h,2-{4-[4-(1H-Indol-4-yl)piperazin-1-yl]butylsulfanyl}-5-trifluoromethylpyridine,1i,2-{4-[4-(1H-Indol-4-yl)piperazin-1-yl]butylsulfanyl}-4,6-dimethylnicotinonitrile,1j,2-{3-[4-(1H-Indol-4-yl)piperazin-1-yl]propylsulfanyl}-5-trifluoromethylpyridine,1k,2-{3-[4-(1H-Indol-4-yl)piperazin-1-yl]propylsulfanyl}-4,6-dimethylnicotinonitrile,1l,2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-6-methylnicotinamide,2a, 2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}nicotinonitrile,2b,2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4-methylpyridine,2c,2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4-methyl-6-(piperidin-1-yl)nicotinonitrile,2d,2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4-trifluoromethyl-6-cyclopropylnicotinonitrile,2e,2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-3-methanesulfonyl-4-methyl-6-phenylpyridine,2f, 2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}nicotinonitrile, 2g,2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-4-methylpyridine, 2h,2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-6-methylnicotinamide, 2i,2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-4-methyl-6-(piperidin-1-yl)nicotinonitrile,2j,2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-4-trifluoromethyl-6-cyclopropylnicotinonitrile,2k,2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-3-methanesulfonyl-4-methyl-6-phenylpyridine,2l,6-Chloro-2-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}4-methylnicotinonitrile,2m,6-Chloro-5-fluoro-2-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}nicotinonitrile,2n,4,6-Dimethyl-2-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}pyrimidine,2o,5-Cyano-4-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}pyrimidine,2p, or5-Cyano-4-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}-6-methylsulfanyl-2-phenylpyrimidine,2q,5-Ethyl-2-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}pyrimidine,2r and2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4-trifluoromethylpyrimidine,2s.
 10. A pharmaceutical composition comprising at least one compoundaccording to claim 1 or claim 9, or a prodrug thereof, in atherapeutically effective amount and in combination with one or morepharmaceutically acceptable carriers or diluents. 11-13. (canceled) 14.A method for the treatment of a disorder or disease of a living animalbody that is responsive to the effect of inhibition of serotonin uptakeand antagonism of 5-HT_(1A) receptors, comprising administering to sucha living animal body a therapeutically effective amount of a compoundaccording to claim 1 or claim
 9. 15. A method for the treatment of adisorder or disease of a living animal body that is responsive to theeffect of 5-HT_(1A) and D₄ receptors, comprising administering to such aliving animal body a therapeutically effective amount of a compoundaccording to claim 1 or claim
 9. 16. A The method of treatment accordingto claim 14 where the disorder or disease is an affective disorder or aneurological disorder.
 17. The method according to claim 14 wherein saidanimal body is a human body.
 18. The method according to claim 14wherein the administered compound is a pharmaceutically acceptableaddition salt.
 19. The method of claim 16 wherein said affectivedisorder is selected from the group consisting of general anxietydisorder, panic disorder, obsessive compulsive disorder, depression,social phobia and eating disorders.
 20. The method of claim 16 whereinsaid neurological disorder is psychosis.
 21. The method of treatmentaccording to claim 15 where the disorder or disease is an affectivedisorder or a neurological disorder.
 22. The method according to claim15 wherein said animal body is a human body.
 23. The method according toclaim 15 wherein the administered compound is a pharmaceuticallyacceptable addition salt.
 24. The method of claim 21 wherein saidaffective disorder is selected from the group consisting of generalanxiety disorder, panic disorder, obsessive compulsive disorder,depression, social phobia and eating disorders.
 25. The method of claim21 wherein said neurological disorder is psychosis.
 26. The compoundaccording to claim 1 wherein the compound is a pharmaceuticallyacceptable addition salt of said compound of formula I.
 27. The compoundaccording to claim 9 wherein the compound is a pharmaceuticallyacceptable addition salt of said compound of formula I.
 28. Thecomposition according to claim 10 wherein said at least one compound isa pharmaceutically acceptable addition salt.